# Regulation of tumor suppression by alpha-ketoglutarate

> **NIH NIH R37** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $489,205

## Abstract

PROJECT SUMMARY
Many common oncogenes and tumor suppressors directly regulate metabolic pathways that support cancer
cell survival, growth and proliferation. Metabolites also contribute to the regulation of the chromatin landscape:
multiple cellular metabolites serve as critical co-substrates of enzymes that deposit or remove chemical
modifications on histones and DNA. Oncogenic mutations in several metabolic enzymes result in the
pathological accumulation of metabolites that interfere with normal maintenance of histone and DNA
modifications. However, absent these specific metabolic mutations, whether the more general cancer-
associated metabolic alterations driven by common oncogenes and tumor suppressors likewise affect the
regulation of the chromatin landscape remains poorly understood. Using mouse models of pancreatic cancer
harboring reversible expression of the tumor suppressor p53, we discovered that p53 controls levels of
intracellular alpha-ketoglutarate (αKG), an obligate co-substrate of a family of αKG-dependent dioxygenases
that includes the ten-eleven (TET) family of DNA methylcytosine oxidases. Restoring p53 function in malignant
pancreatic cancer cells triggered intracellular αKG accumulation, which was both necessary and sufficient to
increase markers of TET activity, induce tumor cell differentiation and blunt tumor progression.
Our findings raise the possibility that p53-mediated accumulation of αKG and concomitant changes in the
chromatin landscape and gene expression profiles contribute to the tumor suppressive function of wild-type
p53. The goal of this work is to determine how wild-type p53 functions to regulate cellular αKG levels in
response to oncogenic stress and how αKG contributes to p53-mediated tumor suppression. We hypothesize
that regulation of metabolic pathways by p53 promotes accumulation of αKG, thereby activating gene
expression programs that safeguard against malignant progression. To address this hypothesis, we will
determine the mechanisms by which p53 regulates αKG (Aim 1); elucidate the pathways through which αKG
induces tumor differentiation (Aim 2), and test whether αKG is a barrier to malignant progression (Aim 3). The
proposed experiments will reveal how metabolic alterations that commonly occur in human tumors contribute
to the maintenance of the malignant state and identify pathways that can be targeted to enforce tumor
suppressive outputs even in malignant cells.

## Key facts

- **NIH application ID:** 10033018
- **Project number:** 1R37CA252305-01
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Lydia Finley
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,205
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033018

## Citation

> US National Institutes of Health, RePORTER application 10033018, Regulation of tumor suppression by alpha-ketoglutarate (1R37CA252305-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10033018. Licensed CC0.

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